Pracyk J B, Slotkin T A
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
J Dev Physiol. 1991 Oct;16(4):251-61.
In mature animals, thyroid hormone produces parallel up-regulation of beta-adrenergic receptor binding sites and their linkage to adenylate cyclase; during development, these same processes may be critical in establishing the set-point for subsequent adrenergic reactivity. In the current study, we administered triiodothyronine to neonatal rats for the first five days postpartum and evaluated [125I]pindolol binding capabilities and adenylate cyclase activity in membrane preparations from heart and kidney. In the heart, hyperthyroidism elicited an initial increase in receptor density, with subsequent deficits and an eventual return to normal values by young adulthood. In contrast, the ability of isoproterenol, a beta-adrenergic agonist, to stimulate adenylate cyclase was enhanced regardless of whether receptor numbers were increased or decreased; the same effects were also present for basal adenylate cyclase activity and non-receptor-mediated stimulation by forskolin. Enhanced cyclase activity involved both increases in the magnitude of response as well as accelerated onset of the postweaning peak of enzyme activity, results which suggest a direct impact of thyroid status on the ontogenetic expression of adenylate cyclase itself. The kidney, which possesses less efficient beta-receptor coupling to adenylate cyclase in the neonate, was less drastically affected by triiodothyronine for either beta-receptor binding sites or enzyme activity. As we had previously shown that neonatal hyperthyroidism uncouples beta-receptors from growth-related enzymes, such as ornithine decarboxylase, we also evaluated whether the promotion of adenylate cyclase responses was mechanistically linked to effect on ornithine decarboxylase; administration of cyclic AMP analogs to 5 days-old rats led to inhibition of the enzyme in the heart, whereas the same treatment in 9 days-old animals was ineffective. These data suggest that thyroid hormone differentially regulates the development of beta-receptors as well as adenylate cyclase and ornithine decarboxylase, with preferential effects on tissues, such as the heart, that already possess efficient linkage of the receptors to cell transduction mechanisms at birth.
在成年动物中，甲状腺激素使β-肾上腺素能受体结合位点及其与腺苷酸环化酶的连接同时上调；在发育过程中，这些相同的过程对于建立随后肾上腺素能反应性的设定点可能至关重要。在本研究中，我们在产后头五天给新生大鼠施用三碘甲状腺原氨酸，并评估心脏和肾脏膜制剂中[125I]吲哚洛尔的结合能力和腺苷酸环化酶活性。在心脏中，甲状腺功能亢进引起受体密度的最初增加，随后出现缺陷，到成年早期最终恢复到正常值。相比之下，β-肾上腺素能激动剂异丙肾上腺素刺激腺苷酸环化酶的能力增强，无论受体数量增加还是减少；基础腺苷酸环化酶活性和福斯可林的非受体介导刺激也有相同的效果。环化酶活性增强既包括反应幅度的增加，也包括断奶后酶活性峰值的起始加速，这些结果表明甲状腺状态对腺苷酸环化酶自身的个体发育表达有直接影响。新生时β-受体与腺苷酸环化酶的偶联效率较低的肾脏，无论是β-受体结合位点还是酶活性，受三碘甲状腺原氨酸的影响都较小。正如我们之前所表明的，新生期甲状腺功能亢进会使β-受体与生长相关酶（如鸟氨酸脱羧酶）解偶联，我们还评估了腺苷酸环化酶反应的促进是否在机制上与对鸟氨酸脱羧酶的影响相关；给5日龄大鼠施用环磷酸腺苷类似物会导致心脏中该酶受到抑制，而在9日龄动物中进行相同处理则无效。这些数据表明，甲状腺激素对β-受体以及腺苷酸环化酶和鸟氨酸脱羧酶的发育有不同的调节作用，对出生时受体已与细胞转导机制有效连接的组织（如心脏）有优先影响。
